Pharmaceutical preparation for relieving itch and killing acaridae



. constant irritation.

Patented Apr. 25, 1950 PHARMACEUTICAL PREPARATION FOR RE- LIEVING ITCHAND KILLING ACARIDAE Henry Martin and Alfred Margot, Basel, Switzerland,sssignors to J. R. Gelgy A. G., Basel, Switzerland, a Swiss firm NoDrawing. Application June 23, 1947, Serial No. 756,550. In SwitzerlandJune 28, 1948 7 Claims.

Acaridae (mites) are widespread pests. Many kinds lead a parasitic lifeon host organisms, such as plants, animals and human beings, causingconsiderable harm. The condition brought about by mite attacks on humansis called scabies or "the itch. Itch mites are parasitic; burrowing andbreeding in the skin, causing eruptions and (See Webster's NewInternational Dictionary under itch mite.") The textbooks on dermatologyprovide substantially the same information. (Consult Becker andObermayer, "Modern Dermatology and Syphilology" (1940) p. 486; Schwartz,Tulipan, and Peck. "ccupational Diseases of the Skin (2nd ed. 1947). p.602; Ormsby and Montgomery, Diseases oi the Skin (6th edition), p.1138.)

Acaridae difler from insects partly by their blology but also haveessential anatomical and physiological dissimilarities. For this reasonit is not astonishing that insecticides show no or only insufiicientaction against Acaridae. For example, the well-knownaza-bis-(p-chlorphenyll- #:pzp-triehlorethane is inactive against mostAcaridae. Also other natural and synthetic insecticides have no markedetlect on Acaridae.

It has now been found that amides of no unsaturated carboiiylic acids oithe general formula wherein R1 and R2 mean hydrogen or methyl, 7

Rs means hydrogen or alkyl and Rt means a phenyl radical, which incertain cases contains substituted. non-saltforming WWW,

are very eiiective for combating Acaridae. Am-

The iollowina compounds have proved to be still edective at aconcentration at illm/cmfl against the red spider (Paratetranychushumm-ili) which is particularly dimcult to combat:

Action: kill Time Compound Percent Hours Crotonic acid-N-lnethyl-aniiide##Dimethylam-yllc acid-N-methyl-unilidai. flfi-llgimethylacryhcacid-N-methyl-ptoluie flfi-Dimethylacrylic acld-N-methyl-o-chloranilldeh Na- Example B The following test results were observed with flourmites (Aleurobius jarinae) and cheese mites (aurogluphus 8110) at aconcentration of 10- g. cm.

Alum. to 2. Compound for. Time i in 'Iimc kills kllls iOrotonicacid-N-methyl- Per cent Hours Per can! Hours anllide 9i 8 160 2Crotonie scid-N-ethylanllide 24 3 Crotonlcacld-N-methylo-toiu e 83 8 838 4 Crotonic aeld-N-ethylo-toiuldldo 91 8 87 8 5 Crotonlcacld-N-methyi-0.5

p-toluidlde 8 ll Crotonicacld-N-methyl- 7 flfillrlontalrlilllide Hum.100 2 100 8 me Mr cac 8i 2 a that? at t "15 mo y y cac N-ethyl-anilide93 M i 100 2 9 flfl-Dimeth lacr licacid- 80 2 w E 'gbniethyg {IO-10uidirlle. s5 24 91 24 as 0.5 87 2 tiiifi'fififl'fffiff; 100 2 92 a llBJtDlmethylaci-ylic acid-N-methyl-o' chloranilide 92 2 90 2 i2Trimethyiacrylic acid- N-methyl-o-toluidide. 75 24 100 Example C The useoi the following compounds in 10% acetone solution resulted in thecomplete extermination of a further type of mite, Psoroptes cuniculi,inside 48 hours:

Compound ,52 M.Pt.C.

7 Orotonic scid-N-ethyl-p-toluia dide 159-163 (11) 9 157-160 (11)anilide 160-173 (is 10 Crotonic acid-N-ethyl-p-broman e 127-130 (0.1) 11Crotonic acid-N-ethyl-3,4-dichioranlll e 138-141 (0.1) l2 Crotonicacid-N-etbyl-Z-chlor-fimethFl-anilide 118-121 (0.05) ..i-.-. 13 Croton cacid-o-anisidide 77-79 14 Crotonic acid-N-methyl-pidide 135-140 (0.-1)15 Crotonic acid-N-ethyl-o-anisido 133-138 (0.15) 16 Crotonicacid-N-boamyl-o-toluididc 134-138 (0.1) 17 3,8- Dimeth lacrylicmethyl-an ide 145-146 (13) 18 5,8 Dimeth lacrylic acid-N- eth l-anili e148-150 (13) 19 0,8- imetbyl-acrylic acid-N- isobutyl-anilide 122-125(0.3)

20 0,8 Dimethylacrylic acid-N- metbyl-o-toluidide 145-150 (12) 21 8,5Dimethyl acrylic acid-N- ethyl-o-tolui de 150-152 (13) 22 3,8 Dimethylacrylic acid-N- isoamyl-o-tol do 126-129 (0.2) 21 3,8 Dimethyl acrylicacid-N- hyl-m-toluidide 155-158 (11) 24 pp Dimethyl acrylic acid-N-ethyi-p-toluidide.-. 160-163 (11) 25 0,3 Dimethyl -scrylic acid-N-methyl-p-toluidide L... 152-155(12) 0,5 Dimethyl acrylicacid-pchloranilide 122-124 27 0,6 Dimethyl acrylic acid-N-cthiyslp-bromamlide 121-126 (0.1) 28 flflimethyl-a iic acid-N-mothyl-o-chioran ide 168-172 (13) 29 5,8 Dimethyl acrylic acid-N--cthyl-m-ch oranilldc 114-116 (0.05) 30 fl,fl- Dimethyl-acrylic acid-N-ethyl-3,4-dichloranilide..... 121-126 (0. 05) 31 5,8 Dimethyl acrylicacid-N- ethgIQ-chIor-G-methyI-amiide.. 117-118 (0.05) 32 5,8-imethyl-acrylic acid-N- cth l-o-anisidide 120-130 (0.2) 33fi,flimethyl-acrylic acid-N- methyl-p-anisidide 134-138 (0. 1) 34 6,0Dimethyl acrylic acid-N- ethyl p-phenetidide.. 143-148 (0.2) 35Trimethyl-acrylic acid-N-methylanilidide 115-119 (0.4) 36Trlmethyl-acryllc acid-N-methylo-toluidide....'. 148-150 (12) 37Trimethyi-acrylic acid-N-ethylo-toluidido 152-156 (12) 38 Trimethl-acrylic acid-N-ethyl- 3 did 153-157 (12) p-toiuidide 153-157 (12) 40Trimetbyl-acrylic acid-N-ethylm-chloranilide 121-125 (0.05) 41Trimethyl-ac lic acld-N-ethylp-bromanili e 121-126 (0. 1) 42 0,8Dimethyl-acr lic acid-dichlor-aniiide ixture oi 43 T11 il "l'i"'l'd1l""ii1"1 M met y-acry cac -me ypanisidido 130-135 (0.1) 44Trimethyl-acrylic acid-N-ethylp-phenetidide 139-143 (0. 1)

It should be noted, however, that in most cases the limit of effectiveconcentration is considerably lower. Furthermore, the mites becomeparalysed in a very short space of time so that already long beforedeath they are unable to cause any more damage. As is explained below,the compounds have bactericidal properties in addition to beingacaricidal. Further since they are practically odouriess and non-toxicin the concentration necessary, they are eminently suitable for thepreparation of acaricidal media for use not only to protect plants andstores, but also for general hygiene.

The active compounds should not be used in their original form butdiluted, thus allowing better and more economical use to be made ofthem. In general, an approximately 5-10% concentratton in the mixture asused has been found sufficient. However, in certain cases, e. g., withaqueous emulsions, it is possible to employ much lower concentrationswith success. In the case 01' preparations in powder form, e. g., mediafor dusting or powdering where contact with the mites is not so intimateas with liquid preparations, higher concentrations up to e. g. 80% canbe utilised. A fine, even dispersion of the active substance in theproduct when ready for use is of importance as regards the eiiiciency orthe medium preparable according to the invention. In concentrates, e.g., concentrated emulsions, which need to be diluted before use, theactive agent must be present in a form which can be dispersed bothrapidly and finely. Such a fine dispersion can be achieved, for example,by mixing and milling the active agent with a solid, pulverulentextending agent to the desired degree of fineness or by impregnating thealready milled, finely powdered, solid carrier with a solution of theactive agent in a volatile solvent and then removing the latter, whichcan be recovered when desired, e. g., by suction at reduced pressure.-The particle size of the final product should notexceed ca. 300 microns.An advantageous particle size is from 20-80 microns.

Such fine dispersions can also be brought about by emulsifying theactive ingredient or a solution or the same with. the aid of adispersing-or emulsifying-agent. In the emulsions the active ingredientis present, dispersed in particles ranging from fine to colloidal size.The particle size should in general not be more than 200 microns. Anadvantageous particle size is, however, below 10 microns.

The invention can also be used in the form of a solution of the activeingredient in suitable inert liquid or semi-solid extending agents wherethe active agent is dispersed in molecular size. The mode of employmentvaries according to the uses intended. As solid carriers, which aresuitable for the manufacture of pulverulent preparations. various inert,porous and pulverulent distributing agents of an inorganic or organicnature may be employed, for example, tricalcium phosphate, 'calciumcarbonate in the form of whiting or ground chalk or limestone, kaolin,bole, bentonite, talcum, calcined magnesia, kieselguhr, boric acid, alsopowdered cork, powdered wood and other pulverulent materials ofvegetable origin are suitable carrier substances. By adding wettingand/or dispersing agents, such pulverulent preparations can be renderedeasily wettable by water so as to obtain stable suspensions suitable foruse as spraying agents, for example, in plant protection.

Inert solvents suitable for the production of liquid preparations shouldnot be easily inflammable and should be as odourless as possible and,when used properly, should be as non-toxic as possible towards men andanimals. Also they should be non-corrosive towards the active componentas well as towards the materials of the storage vessels. The followingsolvents may be employed forthis purpose: On the one hand, high-boilingoils, for example, oils of vegetable origin, such as castor-oil and thelike; on the other hand, also low boiling solvents with a flash point ofat least 30 C., such as, for example, carbon tetrachloride, ethylenedichloride, tetrachlorethane, hydrogenated naphthalenes, alkylatednaphthalenes, solvent naphtha or the like. Obviously, mixtures ofsolvents may also be employed. The preparation of solutions is carriedout in the usual manner, if required, with the aid of solubilitypromoters.

Other practical liquid forms consist of emulsions or suspensions of theactive component in water or suitable inert solvents, or of concentratesfor preparing such emulsions which can be addilution at the place ofuse. For this purpose, the active component is mixed with a dispersingor emulsifying agent. The active component may also be dissolved ordispersed in a suitable inert solvent and mixed at the same time orsubsequently with a dispersing or emulsifying agent. By diluting such aconcentrate, for example with water, emulsions or suspensions ready foruse are obtained. With a suitable concentration and mixing proportion ofactive component, emulsifying agent and water, clear, entirely stableaqueous solutions .(emuisoids) can be obtained.

Various capillarily active substances with an anion-active or acation-active or a non-ionising component may be employed as dispersingor emulsifying agents. There may be mentioned, by way of example,natural or synthetic soaps, Turkey red oil, fatty-alcohol sulphonates,sulphated fats, esters of fatty acids, and the like, also highermolecular quaternary ammonium compounds, as well as condensationproducts of aliphatic or araliphatic compounds and ethylene oxide, forexample, the condensation product of stearin alcohol and ethylene oxide.

For special purposes, semi-solid extenders of the nature of a cream,ointment, paste or wax may be employed. into which the active substancecan be worked, with the aid of solubility-promoters and/or ofemulsifying agents, if required. Such semi-solid preparations are mostlyemulsions. Soft soap (potassium stearate) or Vaseline may be mentionedas examples of semi-solid extenders.

The active component itself may consist of one or more compounds of theformula defined. Also. it may be used together with other organicsynthetic acaricides, insecticides. ovicides, fungicides or bactericidalsubstances. There may be mentioned, by way of example as othersubstances of kind; benzyl benzoate, dimethyl thianthrene,phthalonitrile, a: a-blS- chlorophenyl) -fl1fl :fi-trichlorethane or-fi:,B-dichlorethane (DDT and DDD), dinitrocresol, nitratednaphthylarnine, mercury compounds or inorganic substances such as coppercompounds, sublimate or sulphur. Composite preparations with a greatrange of efiectiveness are obtained in this manner.

It is also possible to employ the active component in the form ofaerosols. For this purpose,

the active component is dissolved or dispersed, with the aid of suitableinert solvents as carrier liquids, if required, in a solvent such asFreon which boils below room temperature at atmospheric pressure. Thereare thus obtained solutions under pressure which, on being sprayed. giveaerosols which are specially suitable for combating mites in closedspaces, in grain silos and other store rooms. The active ingredient, ina suitable solvent, can also be sprayed using compressed gases, e. g.,air.

Thei'ollowing may be mentioned as further additives which can be mixedwith the various forms of composition (Acaridae combating compositions)mentioned: adhesive substances such as casein, salts of fatty acids,glue, resins, fats, albumen-degradation products; wetting agents,solubility promoters, dyestufls and perfumes and, in the case ofpulverulent preparations, dust-binding media and so on. i

It is quite possible, by selecting the various extenders and additives,to give the agents such a composition and properties, depending thereon,as to render them suitable for special purposes or conditions ofemployment. Thus, it is possible to produce, for example, dips,sprinkling agents, and spraying agents in th form of emulsions orsuspensions, as well as emulsions and suspensions for general use andconcentrates for their preparation. The agents mentioned are mostlyliquid preparations. The following are solid preparations: dustingagents, drying powder, strewing agents and such like, and also solidsoap preparations which can be employed in the form of moulded pieces.

The present Acaridae combating agents can be applied by methods ofapplication usual for insecticides. The Acaridae or the materials, forexample, plants, roots, root nodules, drugs, textiles, packingmaterials, cereals, dried fruits, stores of foodstuilfs and fodder,seeds, wood, leather, skins, paper, furs, hair, feathers, articles ofall kinds, carpets, Walls and floors, which are to be treated orprotected from attack by or harbourage oi Acaridae, can be treated withthe active component or with the agents described. by dusting, strewing,sprinkling, painting, smearing, impregnating or other suitable methods.

As mentioned at the beginning, the active compounds having the formuladefined have a strong bactericidal or growth-inhibiting action onvarious sources of infection, such as, e. g.,. Streptococci andStaphylococci. The action on Staphylococcus aureus is revealed in thefollowing experimental results. The tests for bacteriostatic activitywere carried out using a modified plate method due to Flemming:

Inhibition Diameter, mm.

Compound (5 mg. quantities) o h staphylo Streptog cocci cocci bum 1Crotonic acid-N-methyl-otoluidide 144-148/13 7-10 3 o 2 CrotonicacidN-etbyl-o-toluldide. 153-155/13 7-8 10 7 3 Crotonic acid-N-ethyl-ptoluidide. 59 7 4i Crotonic acid-N-ethyl-p-bromanliide. 127-130/0. 1 4-56 5 Crotonie acid-N-ethyl-2-chlor-fi-rnethyl-anilide. 118-121/0. 05 6-77 ti 6 Crotonlc acid-N-methyl-p-anisidide -140/0. l 5 I Crotonicacid-Nethybp-phenetidide 143-147/0. l 7 8 5-5 Dimethvlacrylic acid-Nmethyl anilide... %46/13 5 9 B B-Dimethylacrylic acid-N methyl-otoluidide 145-150/12 7-11 7 7 10 B d Dlmethyiacrylic acid-N-ethyi-otoiu1dide. -152/13 5 6 6 l1 BzB-Dimethylncrylicacid-N-isopropyl-o-toluidIda-.- 116-119/0. 4 6 l2 fl:fl-Dimethyl acrylicacid-N-methyl p toluidide 152-155/12 6-0 6 9 13 B:B-Dimethylacryllcacid-N-ethyl-p-toluidide -163/11 6-7 4 6 14 fizfl-Dimethyl-acrylicocid-N-ethyl-Z-chiortmethyl-anilide 117-119/(105 9-14 5 7 15B:B-Dimethyl-acrylic acid-N-methyl'p-Bnlsidide 134-133/0. 1 B 16Trimethyl-acryllc acid-N-methyl-o-toluidido. 148-150/12 7 i7fl:B-'Irimethylacrylic acid-N-ethyl-m-toluldide 153-157/12 i 18'Irimethyl-acrylic acid-N-ethyln'anlsidide. 168-174/11 6-7 19Trimethyl-acryiic 8cid-N-methyl-p-anisidida. 130-135/0. l 5 20'Irimethyl-acrylic acid-N-ethyl-p-phenetidide 139*143/0. 5 m Comparisoncompound iodo-chloro-oxyquinoline 3-5 Thus the agents prepared accordingto the invention can also be used as disinfectants in the event of adisinfectant action being necessary or desired. Accordingly, articles ofclothing or underwear, implements, utensils and other articles as wellas living-rooms, surgical instruments and adjuvants can all bedisinfected using the agents.

Also, agents which contain the active component herein defined are verysuitable for cleaning and washing warm-blooded animals attacked bymites. The following are particularly suitable extending agents for thispurpose: liquid extenders, e. g., paraflln oil or vegetable oils such asolive oil, castor oil, sesame oil, camphor oil and also glycerine orsolvent-mixtures, e. g., containing glycerine, and so on. Suitablesemi-solid extenders, e. g., Vaseline, wool fat and the like, ormixtures of such materials. Suitable emulsifying agents for thepreparation of aqueous solutions and emulsions, for example, are aboveall soaps, but also sulphonated fats, fatty acid esters and fattyalcohol sulphonates, alkylated aromatic and hydrogenated aromaticsulphonic acids, higher molecular alkoxy carboxylic acids, e. g., alkoxyacetic acids as well as non-ionising emulsifying agents, such ascondensation products of fatty alcohols with ethylene oxide. Esters ofphosphoric acid are also satisfactory emulsifying agents. However,emulsions of ointment-like consistency can be produced, for example byemploying stearic acid, fatty acid salts and water For the production offat-free ointments, cellulose ether bases may be employed, or othersteeping or swelling substances of animal, vegetable or synthetic originand water or inorganic substances, such as aluminium-hydroxide gel, inwhich the active substances can be incorporated,

it necessary with the aid of emulsifying agents and/or solubility agentssuch as parafiln oil. If desired, the preparations obtained may beperfumed by the addition of perfumes. Examples of good, adhesivepulverulent carrier substances are, talcum, starch, lactose and thelike.

Many other solids can also be used as carriers, e. g., textile fabrics,cotton, wool, sheets of paper or water-soluble celluloses, which can befor example impregnated with the active ingredient.

Furthermore, the bactericidal action can be extended by the addition ofphenols, such as pchlor-m-cresol, o-butyl-p-chlorphenol,o-benzylp-chlorphenol, chlorxylenol, cyclohexylphenol, oxydiphenyl andsimilar compounds. The active ingredients may also be combined with manyother disinfectants and fungicides, e. g., with quaternary ammoniumcompounds such as dodecyl-benzyl-trimethyl ammonium metho-sulphate,oxyquinoline derivatives, colloidal silver preparations, thiocyanic acidetc. In special cases an auxiliary substance such as wetting agent canalso have bactericidal action and increase thereby the disinfectantaction of the medium. Foam producing substances are also particularlyeffective for this purpose, such as, e. g.. ordinary or synthetic soaps,saponines and so on.

The amides used as active ingredients show, in part, a high dissolvingpower for other compounds which are themselves only difllcultly solublein the solvents used in the manufacture of acaricidal or disinfectantmedia. Thus it is possible for example, to dissolve up to10% of 5:7-dichlor-B-oxyquinaldine at room temperature in crotonicacid-N-ethyl-o-toluidide.

Various modes of preparation of the acaricidalmediaaswellastheirusesaredescrlbedinthe 8. following examples. 'einvention is not restricted to these examples, however. The part! aregiven throughout by weight,

Example 1 5 parts of crotonic-acid-N-ethyl-o-toluidlde (B. P. at 13 mm.153-155 C.) are ground together with 92 parts of talcum in a ball mill,2 parts of olein are then added, the whole is again ground and isfinally mixed with 1 part of slaked lime. The resulting powder is easilyscattered and has good adhesive power. It can be employed for thedusting of rooms and articles or for the protection of plants. A stillbetter distribution of the active substance over or in the carriermaterial is obtained when the carrier is impregnated with a solution ofthe active substance, in alcohol or acetone, for example, and thesolvent then evaporated.

Example 2 15 parts of crotonic-acid-N-ethyl-o-toluldide are mixed with22.3 parts of kaolin; 4 parts of the sodium salt ofdibutylnaphthalenesulphonic acid, 4 parts of casein and 4.7 parts ofsoda are,

Instead of 15 parts of crotonic-acid-N-ethyl-otoluidide, there may beemployed: 5 parts of crotonic-acid-N-ethyl-o-toluidlde and 10 parts ofDDT a a-biS- (p-chlorophenyl) 8 p p-trichlorethane) or 10 parts ofcrotonicv-acid-N-ethyl-otoluidide and 5 parts of said DDT.

' Example 3 parts of p:,8-dimethylacrylic-acid-N-ethylanilide (melting Pt 43 C.) are finely ground together with 20 parts of talc. Thisconcentrate can be'employed .directly as strewing powder for combatingmites. However,it may be diluted to any desired concentration, e. g.,with bentonite. The addition of .urea gives a strewing-powderparticularly effective for purposes of disinfection.

Such powders, which can also be produced-on other principles aresuitable as dusting agents, for example forcombating mites on human oranimal skin. Powder preparations, for example with a basis ofstarch-flour, may also be employed for combating mites in storehouses,by mixing with grain for example. If necessary, substances may beaddedfor improving adhesion, for which purpose, forexample, an addition of 4%of a liquid fatty acid is suitable.

Example 4 5 parts of crotonic-acid-N-ethyl-o-toluidide or -m-toluidideare dissolved in 95 parts of alkylated naphthalene (Velsicol) andemployed as a household spraying agent.

Example 5 By mixing 10 parts of crotonic-acid-ll-ethyl-otoluidide withparts of olive oil, a clear solution is obtained which can be employedfor combating mites.

Example 6 turns into a stable, presumably colloidal solution (emulsoid)when suflicient water is added to make concentration of the activesubstance about 7%.

As i'atty-acid-ester sulphonate, Turkey-red oil, for example, may beemployed. The proportion of active substance to emulsifier may bevaried: thus, for example, a similar emulsion is obtained on employ ng40 parts of crotonic-acid- N-ethyl-o-toluidide and 60 parts ofemulsifier.

Such solutions or emulsions can be employed with advantage for the mostvarious purposes. Thus. they are suitable for spraying in rooms attackedor threatened by mites. Moreover, articles of different kinds, whichhave been attacked by mites or which to be protected from attack bymites, may be sprayed with, or impregnated by immersion in. thissolution. Sacks made of fabric or paper or other packing materials,which have been impregnated with this solution, are

- suitable for the mitefree storage of provisions or other stores.Similarly, these emulsions may be employed for the protection of plants.

Also, parts of the body of human beings and animals which have beenattacked by mites can be treated with such a solution. For this purpose,the solution can be brushed or smeared on. For treating small animals,it is advantageous to use such a liquid as a bathing liquid.

Example 7 30 parts oi crotonic-acid-N-ethyl-o-toluidide, 30 parts ofxylene and 40 parts of Turkey-red oil are mixed to give a clear solutionwhich can be emulsified in water in any proportion. This emulslop isemployed as in Example 6.

Example 8 A homogeneous paste is obtained by stirring iii) parts ofcrotonic-acid-N-ethyl-o-toluidide with 30 parts of potash soap. Bydiluting this paste with water, an emulsion is obtained which issuitable as a washing liquid with mite-exterminating and disinfectantproperties.

Example 9 3y stirring '1 parts of crotonic-acid-N-ethyl-otoluidide with93 parts of alcoholic soap solution,

' a clear solution is obtained. More concentrated solutions may also beproduced which turn into emulsions on being diluted with water. Insteadof 7 parts of crotonic-acid-N-ethyl-o-toluidide, parts ofcrotonic-acid-N-ethyl-o-toluidide and 2 parts of chloroxylenol may beused, giving a disiniectant washing liquid in dilution with water.

Example 10 ll parts of p-tolyl-dodecyl-trimethy1-ammonium-methosulphateand 49 parts of crotonicacid-N-ethyl-o-toluidide are dissolved in 49.6parts of alcohol. emulsion on dilution with water which is suitable forcombating mites as described in Example 6. It is also effective,however, for disinfecting equipment of all kinds.

Example 11 This clear solution gives an I0 10 mite-exterminating anddisinfectant action is obtained, which is specially suitable fortreating limits of the skin which have been attacked by Example 12 3parts of methyl cellulose are soaked in 90 parts of hot water and theswollen mass obtained is intimately mixed with 7 parts ofcrotonicacid-N-ethyl-o-toluidide. A fat-free acaricidal ointment is thusobtained. Instead of methyl cellulose, other swelling substances, suchas tiiagacanth, gelatins or alginates, may be emp oyed.

Example 13 '1 parts of crotonic-acid-N-methyl-anilide (B. P. at 13 mm.,145-448" C.) are stirred with 93 parts of vaselinum flavum until uniformdistribution is obtained. An ointment with good acaricidal effect isobtained. By diluting with suitable solvents, the ointment can be givena thinner consistency. An ointment with a good bactericidal action isobtained which is also suitable for combating mites, e. g., Tyroglyphus.

Example 14 Elli Examples 15 '3' parts ofcrotonic-acid-N-ethyl-o-toluidide (B. P. at 13 mm., l53-155 C.) aremixed with 8.5 parts of fatty acid-ester-sulphonate and 84.5 parts oiwater. This produces a practically clear, stable, probably colloidalsolution suitable for purposes of disinfection, e. g, of surgical tilinstruments.

Instead of this working-solution, a concentrate may be prepared, e. g.,from parts of crotonlc acid-N-ethyl-o-toluidide and 55 parts of fattyacid-ester-sulphonate. 0n dilution with water there results at first anemulsion which however goes into solution when suflicient water is addedto reduce the concentration of the active component to about "1%. 7

till

Example 16 15 parts of fatty alcohol sulphonate, prepared from a fattyalcohol with a. carbon chain of 6-10 carbon atoms, 7 parts of crotonicacid-N-ethylo-toluidide are mixed with 78 parts of water to give anemulsion suitable, for example, for the disinfection oi living-rooms.

Example l? acid-N-ethyl-o-toluidide, said creamypreparation beingadapted to be spread or smeared directly upon the human skin and overaflected parts to afford relief for such condition after contact withsaid affected parts, said preparation being non-toxic andnon-irritating.

2.A pharmaceutical preparation for treating human skin eruption andirritation, comprising a creamy preparation containing a substantialamount of a, creamy vehicle carrying an active ingredient distributedtherethrough, said active ingredient comprising essentially a carboxylicacid amide of the formula.

R1 and R: represent a member selected from the group consisting ofhydrogen and methyl,

R3 represents a member selected from the group consisting of hydrogenand alkyl, and R4 represents a phenyl radical substituted by no morethan two members selected from the group consisting of hydrogen,halogen, alkyl and alkoxy radicals, and no more than one of said membersbeing methyl,

said creamy preparation being adapted to be spread or smeared directlyupon the human skin and over affected parts to afford relief for suchcondition after contact with said aiiected parts, said preparation beingnon-toxic and nonirritating to such irritated skin and compatible tohuman skin.

3. A pharmaceutical preparation of the character set forth in claim 2wherein the active ingredient is present in the preparation at aconcentration not substantially in excess of 10%.

4. A pharmaceutical preparation for direct application to the skin ofhuman beings and effective in relieving skin irritation such as resultsfrom mite attacks and the like, comprising a substantial amount of avehicle, said vehicle being compatible with human skin. containing anactive ingredient distributed therethrough, said active ingredientcomprising essentially a carboxylic acid amide of the formula R1 and R2represent a member selected from the group consisting of hydrogen andmethyl,

R3 represents a member selected from the group consisting of hydrogenand alkyl, and

R4 represents a phenyl radical substituted b no more than two membersselected from the group consisting of hydrogen, halogen, alkyl andalkoxy radicals, no more than one of said members being methyl.

said preparation being oily, compatible to human skin and being adaptedto be spread or smeared directly upon such skin and over affected partsto-afford relief for such condition after contact with said affectedparts, wherein the active ingredient is present at a concentration ofapproximately 5% to approximateiy 5. A pharmaceutical preparation fortreating human skin eruption and irritation comprising a vehicle, saidvehicle being compatible to human skin, containing an active ingredientdistributed therethrough. said active ingredient comprising 12essentially a carboxylic acid amide of the formula CHr-C C-OO-N-Rawherein R -and R: represent a member selected from the group consistingof hydrogen and methyl, 4 R3 represents a member selected from the groupconsisting of hydrogen and alkyi, and

R4 represents a phenyl radical substituted by no more than two membersselected from the group consisting of hydrogen, halogen, alkyl andalkoxy radicals, and no more than one of said members being methyl,

said preparation being non-toxic and non-irritating to such skin. andbeing adapted to be spread or smeared directly upon such skin and overafiected parts to afford relief for such condition after contact withsaid affected parts, wherein the active ingredient is present in saidpreparation at a concentration of approximately 5% to approximately 10%.

6. A pharmaceutical preparation for treating human skin eruption andirritation, comprising a creamy preparation containing a substantialamount of a creamy vehicle carrying crotonicacid-N-ethyl-anilide, saidcreamy preparation being adapted to be spread or smeared directly uponthe human skin and over affected parts to afford relief for suchcondition-after contact with said afiected parts, said preparation beingnontoxic and non-irritating.

7. A pharmaceutical preparation for treating human skin eruption andirritation, comprising a creamy preparation containing a substantialamount of a. creamy vehicle carrying crotonic acid-N-ethyl-p-toluidide,said creamy preparation being adapted to be spread or smeared directlyupon the human skin and over affected parts to ailord relief for suchcondition after contact with said affected parts, said preparation beingnon-toxic and non-irritating.

HENRY MARTIN. ALFRED MARGOT.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date.

2,166,120 Bousquet July 18, 1939 2,226,672 Smith Dec. 31, 1940 2,239,832Smith Apr. 20, 1941 2,350,324 Coleman June 6, 1944 2,354,193 Bowen July25, 1944 2,368,195. Britten Jan. 30, 1945 OTHER REFERENCES Bischoil:"Ber. Deut. Chem," vol. 34 (1901), pages 2127, 2129, 2130, 2132, 2133and 2134.

Fichter et al.: J. Prak. Chem, Series 2, vol. 74 (1906), pages 318 and325.

Lesser: Drug and Cosmetic Industry, June 1943, vol. 52, No. 6, pages626-627, 690694.

Annand: Bimonthly Progress Report No. 24, Sec. 1, Comm. of Med. Res. ofOil. of Sci. Res. and Devel., June 30, 1945, Subj.: Research onInfections Affecting the Armed Forces. Contract No. OEMcmr-M4331, pages12-15.

Annand: Ibid, Report No, 25, Aug. 31, 1945, pages 15-47.

5. A PHARMACEUTICAL PREPARATION FOR TREATING HUMAN SKIN ERUPTION ANDIRRITATION COMPRISING A VEHICLE, SAID VEHICLE BEING COMPATIBLE TO HUMANSKIN, CONTAINING AN ACTIVE INGREDIENT DISTRIBUTED THERETHROUGH, SAIDACTIVE INGREDIENT COMPRISING ESSENTIALLY A CARBOXYLIC ACID AMIDE OF THEFORMULA